mmg_233_2014_genetics_genomicsfandomcom-20200215-history
Gene Therapy to Treat Obesity
Overview: Obesity, defined as having a body mass index (BMI) of greater than 25, is a serious epidemic in the United States and afar, and can lead to a slew of health risks, such as cancer, diabetes, and cardiovascular disease. While a sedentary lifestyle and poor eating habits both play an enormous role is one's body composition, scientists have begun to identify ways in which ours genes can also predispose us to becoming obese. In particular, the hormones leptin and ghrelin (produced in the gastrointestinal tract and then received by receptors in the brain's hypothalmuss ) which are present in our bodies proportional to the amount of body fat we have, can greatly influence the amounts we eat. Leptin is the hormone that signals that we have had enough to eat, while ghrelin lets us know sustenance is required. Scientists have found that mutations in the leptin-receptor genes, in particular, can cause a person to overeat. Essentially, if not working properly, leptin receptor genes never receive the signal that we have consumed enough calories, so a person can continue to eat well past fullness, leading to obesity. Gene Therapy Strategy: In order to combat the effects of faulty leptin-receptor genes, scientists have begun to experiment with gene therapy, testing out whether leptin can be delivered to genetically-obese and normal-weight immature rodents, as these animals have the same hunger-regulation hormones as humans. It is essential that the rodents be immature, or undeveloped (just after leaving the womb), as developed rodents do not express a long-term response to the leptin treatment. To administer the leptin to the rodents, recombinant techniques are employed, where adeno-associated viruses (AAV) are used as vectors to carry the leptin for injection into the rodents. AAV are nonpathogenic and can infiltrate nondividingg and dividing cells alike, making them an ideal vector. The Overall Process and Outcome of Leptin Gene Therapy: 1. Recombinant AAV encoding leptin (rAAV-leptin) is injected into the cerebral ventricle (brain) of immature rats who are offspring of leptin-resistant parents (predetermined via genetic screening) 2. This injection of leptin into the brain of undeveloped rats gets integrated into their genome and allows for normal signaling between the stomach and the brain. Thus, the receptor for leptin is now functionally correctly and optimally. Control groups are used, where leptin-resistant offspring are not injected, so as to have a comparison between the two progeny. 3. A single injection of rAAV-leptin can prevent weight gain for up to 10 months (the length of the longest such study) 4. The treatment reduced food consumption, and, as a result, BMI and body fat percentage in mice administered the treatment versus those that were not 5. Increased thermogenic energy expenditure occuredd among the rodents injected with rAAV-lep, meaning that the leptin not only decreased appetite, but also promoted fat-burning. Thus, leptin gene therapy has proved promising in preventing weight gain by decreasing energy intake and increasing energy expenditure. Adverse Consequences/Limitations The greatest limitation is the fact that this therapy, while effective on rodents, is not employable for human beings for a number of reasons. For one, "intrathecal administration of rAAV-leptin is not a practical mode of treatment in large populations," as the therapy is highly invasive and has the consequence of being imprecise. Secondly, the long-term effects of central rAAV-leptin on brain structure and function are not known. Therefore, more studies would need to be conducted regarding the long-term effects of this therapy on the rodents. Finally, the irreversibility of the rAAV-leptin gene therapy raises safety and toxicity concerns, and continuous exposure to high leptin levels can cause excessive weight loss. "Theoretically, this obstacle may be overcome by placing the leptin gene under the control of a promoter responsive to signals involved in leptin regulation. Unfortunately, our understanding of how leptin is regulated in the brain is at best rudimentary." Also, for the effectiveness of leptin-therapy to occur, the hormone must be administered to an undeveloped fetus, and most human parents would most likely be wary of any procedure where an injection would need to be made to their baby's brain. While preliminary studies on rodent populations and their response to leptin gene therapy have been fruitful, it still remains unknown just how soon such treatments can be implemented on humans. It would be far more more desirable to find a similar gene therapy that could be administered to developed humans, such as adults with leptin-resistance, and that is what is being researched currently. None the less, studies such as this one conducted on leptin-resistant mice are helping to provide additonall means for combating obesity, seeing how diet and exercise alone seem to be inadequate in treating the problem. By knowing more about the hormones that make us eat or stop eating, and by understanding the genetic factors behind obesity, it is likely that profound headway will be made in this arena within the next twenty-years. References Ahima, RS. Gene Therapy[http://www.nature.com/gt/journal/v10/n3/full/3301920a.html (2002) 10, 196–197. doi:10.1038/sj.gt.3301920] Dube, MG. Diabetes (2013) Wang, Y et al. Leptin Gene Therapy: www.pubmed.gov DiabetesControl.org Images Courtesy of: Indian Journal of Endocrinology and Metabolism Frontiers Journal